Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis

Background: Interferon beta is an effective treatment for relapsing multiple sclerosis (MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment. Objectives: To determine the incidence and biological significance of NAB to interferon beta-1a (IFN-β-1a; Avonex; Biogen, Cambridge, MA) in MS patients. Methods: A two-step assay for NAB to IFN-β-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-β-1a, and from patients in an ongoing open-label study of IFN-β-1a. The biological significance of NAB to IFN-β-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and β- 2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-β-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-β-1a with the incidence in MS patients who had used only IFN-β-1b. Results: In patients in the open-label study, development of NAB to IFN-β-1a resulted in a titer-dependent reduction in neopterin induction after interferon injections. In patients in the phase III study, development of NAB was associated with a reduction in β-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-β-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-β-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-β-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-β-lb for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB. Conclusions: NAB directed against IFN-β have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-β is significantly greater with IFN-β-1b therapy compared with IFN-β- la therapy. Treatment decisions in MS patients treated with IFN-β should take into account development of NAB.